Direct and selective pharmacological disruption of the YAP-TEAD interface by IAG933 inhibits Hippo-dependent and RAS-MAPK-altered cancers

Nat Cancer. 2024 Apr 2. doi: 10.1038/s43018-024-00754-9.

Emilie A Chapeau ¹, Laurent Sansregret ², Giorgio G Galli ², Patrick Chène ², Markus Wartmann ², Thanos P Mourikis ², Patricia Jaaks ², Sabrina Baltschukat ², Ines A M Barbosa ², Daniel Bauer ², Saskia M Brachmann ², Clara Delaunay ², Claire Estadieu ², Jason E Faris ³, Pascal Furet ², Stefanie Harlfinger ² ⁴, Andreas Hueber ², Eloísa Jiménez Núñez ², David P Kodack ³, Emeline Mandon ², Typhaine Martin ², Yannick Mesrouze ², Vincent Romanet ², Clemens Scheufler ², Holger Sellner ², Christelle Stamm ², Dario Sterker ², Luca Tordella ², Francesco Hofmann ² ⁵, Nicolas Soldermann ², Tobias Schmelzle ⁶

Affiliations

1 Novartis BioMedical Research, Basel, Switzerland. emilie.chapeau@novartis.com.
2 Novartis BioMedical Research, Basel, Switzerland.
3 Novartis BioMedical Research, Cambridge, MA, USA.
4 AstraZeneca, Oncology R&D, Cambridge, UK.
5 Pierre Fabre Group, R&D Medical Care, Toulouse, France.
6 Novartis BioMedical Research, Basel, Switzerland. tobias.schmelzle@novartis.com.

PMID: 38565920 DOI: 10.1038/s43018-024-00754-9

Abstract

The YAP-TEAD protein-protein interaction mediates YAP oncogenic functions downstream of the Hippo pathway. To date, available YAP-TEAD pharmacologic agents bind into the lipid pocket of TEAD, targeting the interaction indirectly via allosteric changes. However, the consequences of a direct pharmacological disruption of the interface between YAP and TEADs remain largely unexplored. Here, we present IAG933 and its analogs as potent first-in-class and selective disruptors of the YAP-TEAD protein-protein interaction with suitable properties to enter clinical trials. Pharmacologic abrogation of the interaction with all four TEAD paralogs resulted in YAP eviction from chromatin and reduced Hippo-mediated transcription and induction of cell death. In vivo, deep tumor regression was observed in Hippo-driven mesothelioma xenografts at tolerated doses in animal models as well as in Hippo-altered Cancer models outside mesothelioma. Importantly this also extended to larger tumor indications, such as lung, pancreatic and colorectal Cancer, in combination with RTK, KRAS-mutant selective and MAPK inhibitors, leading to more efficacious and durable responses. Clinical evaluation of IAG933 is underway.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-153811

IAG933

99.81%, YAP-TEAD Inhibitor

YAP; Apoptosis

Cancer

Name
Email *

	Sorry, but the email address you supplied was invalid.